Switching tumor-derived extracellular vesicles off and on via targeted proteolysis to shift toward immunogenic...

Despite compelling evidence that tumor-derived extracellular vesicles (TEVs) exhibit either pro- or antitumorigenic phenotypes, pharmacological efforts have focused primarily on their indiscriminate suppression. Here, we propose a strategy of "switching TEVs off and on" to redirect them toward an immunogenic phenotype. Designed as a nanoproteolysis-targeting chimera (Nano-PROTAC) for TEV reprogramming, EVOTAC is composed of tripartite building blocks that integrate a PROTAC and a photosensitizer via a cancer biomarker-responsive cleavable linker and spontaneously self-assemble into supramolecular nanostructures. Upon biomarker-guided activation preferentially in tumors over normal tissues, EVOTAC initially eliminates TEVs by selectively degrading intracellular proteins involved in extracellular vesicle (EV) biogenesis. Subsequent localized laser irradiation reactivates EV generation, prompting tumor cells to predominantly produce immunogenic TEVs in response to photodynamic therapy (PDT). TEVs generated through this switching-off-and-on strategy independently exert pleiotropic effects by inhibiting tumor growth, migration, and metastasis while increasing mature dendritic cells and cytotoxic T lymphocytes in lymphoid organs and tumor tissues. This TEV-toggling process, therefore, significantly enhances both innate and adaptive immune responses to photoimmunotherapy, which leads to a complete regression of triple-negative breast cancer (TNBC) and prevents metastasis and recurrence. Our study highlights the potential of this therapeutic approach for precise TEV modulation and encourages further exploration, adding new breadth to the growing list of EV-targeting cancer immunotherapy concepts.